Substituted 6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepines as anti-proliferative agents
The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7-6-membered rings linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents. PDDs may be represented by formula (I) and pharmaceutically acceptable salts thereof.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is:
for each A1:
(i) each Y 3 is independently NR 17 , O, or S;
(ii) each Y 4 is CH; and
(iii) each Y 5 is independently CH, C(O)H, N, or S; or
(i) each Y 3 is CH;
(ii) each Y 4 is independently NR 17 , O, or S; and
(iii) each Y 5 is independently CH, C(O)H, N, or S;
for each A2:
(i) each Y 6 is independently CH or N; and
(ii) each Y 7 is CH; or
(i) each Y 6 is CH; and
(ii) each Y 7 is independently CH or N;
X 1 is —CR 13 R 14 —, —, CR 13 R 14 O—, —C(O)—, —C(O)NR 13 —, —C(O)O—, —NR 13 —, —NR 13 C(O)—, —O—, —OC(O)—, or —S—;
L is an amino acid, a peptide chain having 2, 3, 4, 5, or 6 amino acids, —C 1-12 alkylene-, —(OCH 2 ) 1-12 —, or —(OCH 2 CH 2 ) 1-6 —, wherein the C 1-12 alkylene may optionally contain one or more carbon-carbon double bonds or carbon-carbon triple bonds, and further wherein the C 1-12 alkylene, —(OCH 2 ) 1-12 —, and —(OCH 2 CH 2 ) 1-6 —may optionally and independently be interrupted by one or more atoms or groups independently selected from the group consisting of —NH—, —O—, —S—, phenylene, and C 5-9 heteroarylene;
X 2 is absent; or
X 2 is —CR 15 R 16 —, —CR 15 R 16 O—, —C(O)—, —C(O)NR 15 —, —C(O)O—, —NR 15 —, —NR 15 C(O)—, —O—, —OC(O)—, or —S—;
Y 1 is CH or N;
Y 2 is CH or N;
R 1 is R 7 , (CH 2 ) m —C(O)R 7 , (CH 2 ) m —C(O)NR 7 R 8 , (CH 2 ) m —C(O)OR 7 , (CH 2 ) m —NR 7 R 8 , (CH 2 ) m —OR 7 , (CH 2 ) m —S(O) 2 R 7 , ═CH 2 , ═CH—(CH 2 ) m —CH 3 , NHC(O)R 7 , O—(CH 2 ) n —C(O)NHR 7 , O—(CH 2 ) n −NR 7 R 8 , O—(CH 2 ) n —NHC(O)R 7 , OS(O) 2 R 7 , or ═O;
R 2 is R 9 , (CH 2 )—C(O)R 9 , (CH 2 )—C(O)NR 9 R 10 , (CH 2 )—C(O)OR 9 , (CH 2 ) r —NR 9 R 10 , (CH 2 ) r —OR 9 , (CH 2 ) r —S(O) 2 R 9 , ═CH 2 , ═CH—(CH 2 ) m —CH 3 , NHC(O)R 9 , O—(CH 2 ) s —C(O)NHR 9 , O—(CH 2 ) s —NR 9 R 10 , O—(CH 2 ) s —NHC(O)R 9 , OS(O) 2 R 9 , or ═O;
R 3 is H, C 1-12 alkyl, or CH 2 -phenyl;
R 4 is phenyl or C 5-9 heteroaryl, each optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, (CH 2 ) j —C(O)OR 11 , (CH 2 ) j —NR 11 R 12 , C(O)—NHR 24 , C(O)—NH(CH 2 ) k —C(NH)NR 11 R 12 , C(O)—NH(CH 2 ) k —NR 11 R 12 , OH, OC 1-6 alkyl, and O—(CH 2 ) k —NR 11 R 12 ;
R 24 is phenyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, (CH 2 ) j —C(O)OR 11 , (CH 2 ) j —NR 11 R 12 , C(O)—NHR 24 , C(O)—NH(CH 2 ) k —C(NH)NR 11 R 12 , C(O)—NH(CH 2 ) k —NR 11 R 12 , OH, OC 1-6 alkyl, and O—(CH 2 ) k —NR 11 R 12 ;
R 5 is H; and
R 6 is OH or OC 1-6 alkyl; or
R 5 and R 6 together form a double bond;
R 7 is H, C 1-12 alkyl, C 7-12 aralkyl, C 6-15 heteroarylalkyl, phenyl, or C 5-9 heteroaryl, wherein the aralkyl, heteroarylalkyl, phenyl, and heteroaryl are each optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, OH, and OC 1-6 alkyl;
R 8 is H or C 1-6 alkyl;
R 9 is H, C 1-12 alkyl, C 7-12 aralkyl, C 6-15 heteroarylalkyl, phenyl, or C 5-9 heteroaryl, wherein the aralkyl, heteroarylalkyl, phenyl, and heteroaryl are each optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, OH, and OC 1-6 alkyl;
R 10 is H or C 1-6 alkyl;
R 11 is H or C 1-6 alkyl;
R 12 is H or C 1-6 alkyl;
R 13 is H or C 1-6 alkyl;
R 14 is H or C 1-6 alkyl;
R 15 is H or C 1-6 alkyl;
R 16 is H or C 1-6 alkyl;
R 17 is H or C 1-6 alkyl;
R 19 is H or (CH 2 ) t —NR 20 R 21 ;
R 20 is H or C 1-6 alkyl;
R 21 is H or C 1-6 alkyl;
j is 0, 1, 2, 3, 4, 5, or 6;
k is 1, 2, 3, 4, 5, or 6;
m is 0, 1, 2, 3, 4, 5, or 6;
n is 1, 2, 3, 4, 5, or 6;
p is 0 or 1;
q is 1, 2, 3, 4, 5, or 6;
r is 0, 1, 2, 3, 4, 5, or 6;
s is 1, 2, 3, 4, 5, or 6;
t is 0, 1, 2, 3, 4, 5, or 6; and
the dotted lines indicate the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4;
with the provisos that:
(1) R 4 is not optionally substituted indolyl;
(2) at least one of Yi and Y 2 is CH; and
(3) when p is 0 and A is Al, then:
(a) R 4 is not optionally substituted imidazolyl or optionally substituted pyrrolyl;
(b) for at least one Al, one of Y 3 and Y 4 is 0 or S; or
(c) for at least one Al, Y 5 is S.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a peptide chain having 2, 3, 4, 5, or 6 amino acids, —C 1-12 alkylene—, —(OCH 2 ) 1-12 —, or —(OCH 2 CH 2 ) 1-6 —, wherein the C 1-12 alkylene may optionally contain one or more carbon-carbon double bonds or carbon-carbon triple bonds, and further wherein the C 1-12 alkylene, —(OCH 2 ) 1-12 —, and —(OCH 2 CH 2 ) 1-6 —may optionally and independently be interrupted by one or more atoms or groups independently selected from the group consisting of —NH—, —O—, —S—, phenylene, and C 5-9 heteroarylene.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is R 7 , O—(CH 2 ) n —C(O)NHR 7 , or O—(CH 2 ) n —NHC(O)R 7 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is CH 3 or CH 2 CH 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is phenyl, pyrrolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, (CH 2 ) j —C(O)OR 11 , (CH 2 ) j —N 11 R 12 , C(O)—NHR 24 , C(O)—NH(CH 2 ) k —C(NH)NR 11 R 12 , C(O)—NH(CH 2 ) k —NR 11 R 12 , OH, OC 1-6 alkyl, and O—(CH 2 ) k —NR 11 R 12 ;
R 24 is phenyl, substituted with one (CH 2 ) j —R 18 ; and
R 18 is C(O)OR 11 or NR 11 R 12 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is selected from the group consisting of:
Z 1 is —NH—, —N(CH 3 )—, —O—, or —S—;
Z 2 is CH or N;
Z 3 is —O— or —S—;
Z 4 is CH or N;
R 22 is (CH 2 ) j —C(O)OR 11 , (CH 2 ) j —NR 11 R 12 , or C(O)—NHR 24 ;
R 23 is H or C 1-6 alkyl;
R 24 is phenyl, substituted with one (CH 2 ) j —R 18 ; and
R 18 is C(O)OR 11 or NR 11 R 12 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 together form a double bond.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 24 is phenyl, substituted with one (CH 2 ) j —R 18 ; and
R 18 is C(O)OR 11 or NR 11 R 12 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
A is:
for each A1:
each Y 3 is N(CH 3 );
each Y 4 is CH;
for each A2:
each Y 6 is CH; and
each Y 7 is CH;
X 1 is —O—;
L is —C 1-12 alkylene—, optionally interrupted by one or more atoms or groups independently selected from the group consisting of phenylene and C 5-9 heteroarylene;
X 2 is —C(O)NH—;
R 1 is H;
R 2 is H;
R 3 is CH 3 ; and
the dotted lines indicating the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4 are absent.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, (CH 2 ) j —C(O)OR 11 , (CH 2 ) j —NR 11 R 12 , C(O)—NHR 24 , C(O)—NH(CH 2 ) k —C(NH)NR 11 R 12 , C(O)—NH(CH 2 ) k —NR 11 R 12 , OH, OC 1-6 alkyl, and O—(CH 2 ) k —NR 11 R 12 .
13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, thiophenyl, oxazolyl, thiazolyl, benzothiophenyl, or benzothiazolyl, each optionally substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, (CH 2 ) j —C(O)OR 11 , (CH 2 ) j —NR 11 R 12 , C(O)—NHR 24 , C(O)—NH(CH 2 ) k —C(NH)NR 11 R 12 , C(O)—NH(CH 2 ) k —NR 11 R 12 , OH, OC 1-6 alkyl, and O—(CH 2 ) k —NR 11 R 12 .
14. The compound of claim 1 , wherein the compound is of formula (XV):
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is of formula (XVI), formula (XVII), formula (XVIII), or formula (XIX):
or a pharmaceutically acceptable salt thereof, wherein:
L is —C 1-12 alkylene—;
each Y 5 is independently CH or N;
Z 1 is —NH—, —N(CH 3 )—, —O—, or —S—;
Z 2 is CH or N;
Z 3 is —O— or —S—;
Z 4 is CH or N;
R 22 is (CH 2 ) j —C(O)OH, (CH 2 ) j —C(O)OC 1-6 alkyl, (CH 2 ) j —NR 11 R 12 , or C(O)—NHR 24 ;
R 23 is H or C 1-6 alkyl;
R 24 is phenyl, substituted with one (CH 2 ) j —R 18 ; and
R 18 is C(O)OR 11 or NR 11 R 12 ;
with the proviso that when the compound is of formula (XVI) and p is 0, then Z 1 is —O— or —S—.
16. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.
18. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.